GASTROENTEROLOGY 2012;143:1218 –1226
`
`Once-Daily Budesonide MMX® Extended-Release Tablets Induce
`Remission in Patients With Mild to Moderate Ulcerative Colitis: Results
`From the CORE I Study
`WILLIAM J. SANDBORN,* SIMON TRAVIS,‡ LUIGI MORO,§ RICHARD JONES,§ THERES GAUTILLE,储 ROBERT BAGIN,储
`MICHAEL HUANG,储 PHIL YEUNG,储 and E. DAVID BALLARD II储
`
`*University of California San Diego, La Jolla, California; ‡Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, England; §Cosmo Pharmaceuticals SpA,
`Lainate, Italy; and 储Santarus, Inc, San Diego, California
`
`CLINICAL AT
`
`BACKGROUND & AIMS: Budesonide is a corticoste-
`roid with minimal systemic corticosteroid activity due to
`first-pass hepatic metabolism. Budesonide MMX® is a
`once-daily oral formulation of budesonide that extends
`budesonide release throughout the colon using multi-
`matrix system (MMX) technology. METHODS: We per-
`formed a randomized, double-blind, double-dummy, place-
`bo-controlled trial to evaluate the efficacy of budesonide
`MMX for induction of remission in 509 patients with active,
`mild to moderate ulcerative colitis (UC). Patients were ran-
`domly assigned to groups that were given budesonide MMX
`(9 mg or 6 mg), mesalamine (2.4 g, as reference), or placebo
`for 8 weeks. The primary end point was remission at week 8.
`RESULTS: The rates of remission at week 8 among subjects
`given 9 mg or 6 mg budesonide MMX or mesalamine were
`17.9%, 13.2%, and 12.1%, respectively, compared with 7.4%
`for placebo (P ⫽ .0143, P ⫽ .1393, and P ⫽ .2200). The rates
`of clinical improvement at week 8 among patients given 9
`mg or 6 mg budesonide MMX or mesalamine were 33.3%,
`30.6%, and 33.9%, respectively, compared with 24.8% for
`placebo (P ⫽ .1420, P ⫽ .3146, and P ⫽ .1189). The rates of
`endoscopic improvement at week 8 among subjects given 9
`mg or 6 mg budesonide MMX or mesalamine were 41.5%,
`35.5%, and 33.1%, respectively, compared with 33.1% for
`placebo. The rates of symptom resolution at week 8 among
`subjects given 9 mg or 6 mg budesonide MMX or mesala-
`mine were 28.5%, 28.9%, and 25.0%, respectively, compared
`with 16.5% for placebo (P ⫽ .0258, P ⫽ .0214, and P ⫽
`.1025). Adverse events occurred at similar frequencies among
`groups. CONCLUSIONS: Budesonide MMX (9 mg) was
`safe and more effective than placebo in inducing remis-
`sion in patients with active, mild to moderate UC.
`ClinicalTrials.gov, Number: NCT00679432.
`
`Keywords: Inflammatory Bowel Disease; Clinical Trial Re-
`sult; Inflammation; Colon.
`
`Ulcerative colitis (UC) is a chronic, idiopathic, im-
`
`mune-mediated inflammatory disease of the colon.1
`Systemic corticosteroids are effective for the treatment of
`patients with active UC.2– 4 However, serious adverse events
`(AEs) associated with systemic corticosteroid therapy pre-
`clude their use as first-line therapy, and corticosteroid ther-
`apy is typically reserved for patients who have failed to
`respond to mesalamine and those who have severe disease.5,6
`
`Corticosteroids can be administered topically as rectal ene-
`mas to reduce systemic exposure and toxicity, but these
`enema formulations are primarily used in patients with
`distal UC or ulcerative proctitis, and patient acceptance is
`limited.7,8 An orally administered topical corticosteroid
`formulation with reduced systemic exposure would be of
`value for the management of active, mild to moderate UC.
`Budesonide is a potent corticosteroid that can be ad-
`ministered topically with minimal systemic corticosteroid
`activity due to nearly 90% first-pass metabolism in the
`liver to metabolites with minimal or no corticosteroid
`activity.9 –11 Controlled ileal release budesonide formula-
`tions (Entocort; AstraZeneca, Wilmington, DE), Budeno-
`falk (Dr Falk Pharma, Freiburg, Germany) release in the
`distal ileum and right colon and are effective at a 9-mg
`dose for induction of remission12–16 and at a 6-mg dose
`for prolongation of time to relapse in patients with mild
`to moderate Crohn’s disease involving the terminal ileum
`and right colon.17–20 These formulations do not deliver
`budesonide to the left colon and therefore are not opti-
`mally designed for the treatment of patients with UC. An
`investigational formulation of oral budesonide designed
`for the treatment of patients with UC suggested possible
`efficacy but was not further developed.21 Budesonide
`MMX® (Cosmo Pharmaceuticals SpA, Lainate, Italy) is a
`novel, once-daily oral formulation of budesonide that
`uses a multi-matrix system (MMX) technology to extend
`the release of budesonide throughout the colon.22,23 A
`randomized pilot study showed that budesonide MMX
`delivered budesonide throughout the colon and might be
`effective for the treatment of active UC.24
`We designed an 8-week, placebo-controlled, dose-find-
`ing induction trial of budesonide MMX in patients with
`active, mild to moderate UC.
`
`Materials and Methods
`All authors had access to the study data and reviewed
`and approved the final manuscript.
`
`Abbreviations used in this paper: AE, adverse event; CI, confidence
`interval; ITT,
`intention-to-treat; MMX, multi-matrix system; OR, odds
`ratio; UCDAI, Ulcerative Colitis Disease Activity Index.
`© 2012 by the AGA Institute
`0016-5085/$36.00
`http://dx.doi.org/10.1053/j.gastro.2012.08.003
`
`
`
`
`
`Cosmo Ex. 2007-p. 1
`Argentum v Cosmo
`IPR2018-00080
`
`

`

`CLINICALAT
`
`November 2012
`
`Patients
`This phase 3, multicenter, randomized, double-blind,
`double-dummy, placebo-controlled trial was conducted at 108
`centers in North America and India between August 2008 and
`May 2010. The protocol was approved by the institutional review
`board for each center. All patients gave written consent.
`Eligible patients were adults up to 75 years of age with active,
`mild to moderate UC for at least 6 months, with an Ulcerative
`Colitis Disease Activity Index (UCDAI) score of 4 –10 points.25,26
`The UCDAI is a composite score of 4 items (stool frequency,
`rectal bleeding, mucosal appearance, and physician’s rating of
`disease activity). For the baseline scoring of the rectal bleeding
`and stool frequency items, the worst score from the previous 7
`days of diary data before day 1 was used. The diagnosis of UC
`was histologically confirmed from a biopsy specimen obtained at
`the baseline colonoscopy and read by a blinded central reader.
`Because the turnaround time for the histologic central reading
`was several weeks, the presence of active UC by histology was not
`an eligibility criterion, but rather was used to define the modi-
`fied intention-to-treat (ITT) population (see the following text).
`Concurrent therapy for UC was not permitted during the study.
`Patients receiving oral mesalamine or other oral 5-aminosalicylic
`acid medications at the screening visit were required to wash out
`of their medication at least 2 days before randomization.
`Patients were excluded from study entry if they had any of the
`following: use of oral or rectal corticosteroids within 4 weeks of
`screening, use of immunosuppressive agents within 8 weeks of
`screening, use of anti–tumor necrosis factor ␣ agents (inflix-
`imab, adalimumab) within 3 months of screening, or participa-
`tion in experimental therapeutic studies in the past 3 months.
`Patients were also excluded for the following: diagnosis of severe
`UC (UCDAI ⬎10 points); evidence or history of toxic megaco-
`lon; disease limited to the rectum (proctitis extending from the
`anal verge up to 15 cm); presence of infectious colitis; presence
`of severe anemia, leukopenia, or granulocytopenia; verified, pre-
`sumed, or expected pregnancy or ongoing lactation; presence of
`cirrhosis or evident hepatic or renal disease or insufficiency;
`presence of severe diseases in other organs and systems; local or
`systemic complications or other pathological states requiring
`therapy with corticosteroids and/or immunosuppressive agents;
`type 1 diabetes; glaucoma; or known infection with hepatitis B
`or C or with human immunodeficiency virus.
`
`Study Design
`This was a multicenter, randomized, double-blind, dou-
`ble-dummy, parallel group, 8-week study comparing budesonide
`MMX® 9 mg or 6 mg tablets with placebo in patients with active
`mild to moderate UC. The choice of the 9-mg dose strength for
`budesonide MMX was based on a pilot phase 2 budesonide
`MMX study that showed numerically favorable efficacy results in
`the 9-mg dose strength versus placebo.24 In addition, the 9-mg
`dose strength has been established as the optimal dose for
`controlled ileal release budesonide (Entocort EC) in Crohn’s
`disease (based on both efficacy and safety data), and dosages
`greater than 9 mg/day did not result in incremental efficacy but
`did increase the potential risk for corticosteroid-related side
`effects.12 The 6-mg dose strength was included as an additional
`treatment arm, at the request of regulatory authorities, to estab-
`lish the lowest effective dose for budesonide MMX in inducing
`remission in active mild to moderate UC. A nonpowered refer-
`ence arm using Asacol 2.4 g (Warner Chilcott plc, Dublin,
`Ireland) was also included as active control and internal refer-
`
`BUDESONIDE MMX® FOR INDUCTION OF REMISSION IN UC 1219
`ence. Patients were randomly assigned to receive one of 4 treat-
`ments: placebo, oral budesonide MMX 9 mg once daily, oral
`budesonide MMX 6 mg once daily, or oral Asacol 2.4 g/day
`(administered as two 400-mg tablets 3 times daily [US formula-
`tion, Procter & Gamble Pharmaceuticals, Cincinnati, OH]) for 8
`weeks. Randomization for this study was developed by an exter-
`nal contractor and administered centrally (not within site) via an
`interactive voice response system. Patients were randomized to
`one of 4 treatments at a 1:1:1:1 ratio using a block size of 4. As
`each new patient was randomized via the interactive voice re-
`sponse system, he or she was given the next available random-
`ization number that was associated with a study drug. Patients
`were followed up through week 10. A follow-up safety visit was
`to be conducted 2 weeks after the final visit (week 8 or early
`withdrawal). The interactive voice response system was used to
`centrally randomize patients to study drug. A double-dummy
`procedure was used to maintain blinding, with patients in each
`treatment group receiving their blinded study drug 3 times daily.
`
`Efficacy Evaluations
`Patients were evaluated at screening; at weeks 0 (base-
`line), 2, 4, and 8; and at early termination. The UCDAI score was
`determined at screening and week 8 and included the use of
`colonoscopy at both visits to evaluate disease severity and treat-
`ment efficacy.25,26 Remission was defined as combined clinical
`and endoscopic remission with a UCDAI score ⱕ1 point, with
`subscores of 0 for both rectal bleeding and stool frequency
`(based on the 3 days closest to the week 8 visit with nonmissing
`diary data within a 5-day window closest to the visit [the 5 days
`did not include any days on which a colonoscopy or the prep-
`aration for colonoscopy occurred]), no mucosal friability on
`colonoscopy, and a ⱖ1-point reduction from baseline in the
`endoscopic index score.27 This definition is very similar to the
`definition of remission used to show the efficacy of MMX
`mesalamine.28,29 Clinical improvement was defined as a ⱖ3-
`point reduction in the UCDAI score. Endoscopic improvement
`was defined as a ⱖ1-point reduction in the UCDAI mucosal
`appearance subscore. This definition or a very similar definition
`has been used in multiple previous clinical trials.25,26,28 –31 Symp-
`tom resolution was defined as a score of 0 for both rectal
`bleeding and stool frequency subscores from the UCDAI.25,26
`Histologic healing was defined as a histologic score of ⱕ1
`(corresponding to a histologic activity grade of 0) according to
`the Saverymuttu scale.32
`
`Safety Evaluations
`At each clinic visit from screening to week 10 or early
`termination, patients underwent physical examination, measure-
`ment of vital signs, review of previous (at baseline) and concom-
`itant medications, and assessment for AEs. General laboratory
`tests, morning plasma cortisol levels, and urinalyses were per-
`formed at screening, weeks 2 and 4, and final visit (defined as
`week 8 or early withdrawal). Potential glucocorticoid effects were
`assessed at screening, week 4, and final visit.
`
`Statistical Methods
`The primary efficacy end point was combined clinical
`and endoscopic remission at week 8. Secondary and other effi-
`cacy end points included clinical improvement, endoscopic im-
`provement, symptom resolution, and histologic healing. Demo-
`graphics and baseline characteristics were summarized using
`descriptive statistics. Efficacy analyses were performed in the
`modified ITT population, which included all randomized pa-
`
`
`
`
`
`Cosmo Ex. 2007-p. 2
`Argentum v Cosmo
`IPR2018-00080
`
`

`

`1220 SANDBORN ET AL
`
`GASTROENTEROLOGY Vol. 143, No. 5
`
`tients who received at least one dose of a study drug and
`excluded patients with major good clinical practice or entry
`criteria violations (enteric infection during screening) and those
`with normal histology at baseline (defined as a histology score of
`0 or 1) as determined by central histopathology review. A sensi-
`tivity analysis was also performed for the primary efficacy anal-
`ysis in which these excluded patients were included in the
`analysis and considered to be treatment failures. The percent-
`ages of patients achieving combined clinical and endoscopic
`remission in both the 9-mg and 6-mg budesonide MMX®
`groups were compared with the percentage of patients receiving
`placebo achieving combined clinical and endoscopic remission,
`using the ␹2 test at the ␣⫽ .025 level of significance to adjust for
`multiple comparisons. A hierarchical testing procedure was used
`for the analysis of both secondary end points at the ␣ ⫽ 0.025
`level of significance. If at least one primary end point compari-
`son was statistically significant, then both dosage strengths were
`compared with placebo with respect to the first secondary end
`point (clinical improvement). If at least one secondary end point
`comparison for clinical improvement was statistically signifi-
`cant, then both dosage strengths were compared with placebo
`with respect to the second secondary end point (endoscopic
`improvement). If at least one primary end point comparison was
`statistically significant, remission rates between budesonide
`MMX and placebo were compared, adjusting for region (Canada,
`United States [and Mexico], and India), age (median age at
`randomization or younger, older than median age at random-
`ization), and sex using the Cochran–Mantel–Haenszel test.
`An analysis of all other end points was conducted using the
`modified ITT population at the ␣ ⫽ .05 level of significance for
`the statistically significant dosage strength(s) for the primary
`end point comparison without adjustment for multiple compar-
`isons. Therefore, the reported P values are nominal P values, and
`these analyses should be considered exploratory. Treatment-
`emergent adverse events were summarized using descriptive sta-
`tistics for the safety population, which included all patients who
`received at least one dose of study drug during the study.
`Patients with missing or incomplete data at week 8 were con-
`sidered not to be in remission or to have clinical improvement,
`endoscopic improvement, symptom resolution, or histologic
`healing.
`
`Sample Size
`Assuming a difference of 20 percentage points between
`at least one budesonide MMX treatment group (estimated re-
`mission rate of 47%) and placebo (estimated remission rate of
`27%) at week 8, 110 patients per group provided 80% power to
`detect a statistically significant difference between at least one
`budesonide MMX treatment group and placebo at the 2-sided
`␣ ⫽ .025 level of significance. Assuming a dropout rate of
`approximately 10%, 123 patients per group or 492 patients total
`were to be randomized in this study. The study was not powered
`to detect a statistically significant difference between the budes-
`onide MMX and Asacol groups.
`
`Results
`Patients
`Supplementary Figure 1 shows the disposition of
`patients. A total of 489 patients were included in the
`modified ITT population. Twenty randomized patients
`were excluded from the modified ITT analysis because of
`
`normal histology at baseline (17 patients) or major entry
`criteria violations (3 patients with confirmed infectious
`colitis at study entry). The baseline characteristics were
`similar across the treatment groups, except that the per-
`centage of male patients in the budesonide MMX 9 mg
`group was somewhat higher (62.6%) than that of the other
`groups (48.8%–56.2%) (Table 1).
`
`Efficacy
`Primary end point. The percentage of patients
`achieving combined clinical and endoscopic remission in
`the budesonide MMX 9 mg group was significantly
`greater than the percentage of patients in the placebo
`group (17.9% vs. 7.4%, P ⫽ .0143 [95% confidence interval
`{CI}, 2.2–18.7]; odds ratio [OR], 2.71 [95% CI, 1.19 – 6.16])
`(Figure 1A). The combined clinical and endoscopic remis-
`sion rates for budesonide MMX 6 mg (13.2% vs 7.4%, P ⫽
`.1393 [95% CI, ⫺1.8 to 13.4]; OR, 1.90 [95% CI, 0.80 –
`4.48]) and Asacol (12.1% vs 7.4%, P ⫽ .2200 [95% CI, ⫺2.7
`to 12.1]; OR, 1.71 [95% CI, 0.72– 4.08]) were numerically
`greater than placebo, but the differences did not reach
`statistical significance (Table 2). An analysis of clinical
`and endoscopic remission using the Cochran–Mantel–
`Haenszel test indicated that the difference between budes-
`onide MMX 9 mg and placebo remained statistically sig-
`nificant after adjusting for age, sex, and geographic
`region. In North American centers, the combined clinical
`and endoscopic remission rates in the placebo, budes-
`onide MMX 9 mg, budesonide MMX 6 mg, and Asacol
`groups were 4.9%, 14.5%, 11.3%, and 9.8%, respectively. In
`the Indian centers, the clinical and endoscopic remission
`rates in the placebo, budesonide MMX 9 mg, budesonide
`MMX 6 mg, and Asacol groups were 12.8%, 25.0%, 17.1%,
`and 16.7%, respectively. Subgroup analyses were per-
`formed for the mutually exclusive categories of proctosig-
`moiditis, left-sided disease (up to the splenic flexure), and
`extensive disease (beyond the splenic flexure). In patients
`with proctosigmoiditis, the clinical and endoscopic remis-
`sion rate for budesonide MMX 9 mg was numerically
`greater than placebo (23.5% vs. 12.2%, P ⫽ .1967). For
`left-sided disease, the clinical and endoscopic remission
`rate for budesonide MMX 9 mg was significantly higher
`than for placebo (31.3% vs 5.9%, P ⫽ .0076). For extensive
`disease, no significant differences in clinical and endo-
`scopic remission rates were observed between budesonide
`MMX 9 mg and placebo (7.1% vs 5.0%, P ⫽ 1.000). A
`sensitivity analysis in which all patients excluded in the
`modified ITT population were included and considered to
`be treatment failures showed results that were similar to
`analysis in the modified ITT population (Supplementary
`Table 1).
`Secondary end points. The percentages of pa-
`tients achieving clinical improvement and endoscopic im-
`provement were both numerically greater in the budes-
`onide MMX 9 mg group than in the placebo group (Table
`2). Clinical improvement was achieved by 33.3% (P ⫽
`.1420), 30.6% (P ⫽ .3146), and 33.9% (P ⫽ .1189) of
`patients in the budesonide MMX 9 mg, budesonide MMX
`
`CLINICAL AT
`
`
`
`
`
`Cosmo Ex. 2007-p. 3
`Argentum v Cosmo
`IPR2018-00080
`
`

`

`November 2012
`
`BUDESONIDE MMX® FOR INDUCTION OF REMISSION INUC 1221
`
`Table 1. Baseline Demographics and Clinical Characteristics
`
`Placebo
`(n = 121)
`
`Budesonide MMX9mg
`(n = 123)
`
`Budesonide MMX6 mg
`(n = 121)
`
`__Asacol 2.4 g
`(n = 124)
`
`Total
`(N = 489)
`
`Age(y)
`Median
`Minimum, maximum
`Sex, n (%)
`Male
`Female
`Race, n (%)
`White
`Black
`Hispanic or Latino
`Asian
`Other
`Disease extent, n (%)
`Proctosigmolditis
`Left-sided colitis
`Extensive/pancolitis
`Missing
`Numberofflares In past 2 years
`Median
`Minimum, maximum
`Severity of lastflare, n (%)
`Mild
`Moderate
`Missing
`Baseline UCDAI score?
`Median
`Minimum, maximum
`Missing
`Baseline endoscopic index score?’
`Median
`Minimum, maximum
`Prior mesalamine use
`Prior any 5-ASA use®
`
`39
`18, 77
`
`68 (56.2)
`53 (43.8)
`
`64 (52.9)
`7 (5.8)
`9 (7.4)
`39 (32.2)
`2 (1.7)
`
`41 (33.9)
`34 (28.1)
`40 (33.1)
`6
`
`2.0
`0, 24
`
`30 (24.8)
`79 (65.3)
`12
`
`7.0
`1,11
`13
`
`7.0
`0, 12
`74 (61.2)
`82 (67.8)
`
`42
`19, 68
`
`77 (62.6)
`46 (37.4)
`
`60 (48.8)
`9 (7.3)
`8 (6.5)
`44 (35.8)
`2 (1.6)
`
`34 (27.6)
`32 (26.0)
`56 (45.5)
`1
`
`2.0
`0, 90
`
`31 (25.2)
`82 (66.7)
`10
`
`7.0
`2, 10
`9
`
`7.0
`3,12
`58 (47.2)
`69 (56.1)
`
`43
`18, 75
`
`59 (48.8)
`62 (51.2)
`
`60 (49.6)
`11 (9.1)
`7 (5.8)
`42 (34.7)
`1 (0.8)
`
`28 (23.1)
`41 (33.9)
`50 (41.3)
`2
`
`3.0
`0, 30
`
`29 (24.0)
`80 (66.1)
`12
`
`6.0
`2,11
`6
`
`7.0
`1,12
`76 (62.8)
`89 (73.6)
`
`CLINICALAT
`
`45
`18, 72
`
`69 (55.6)
`55 (44.4)
`
`61 (49.2)
`8 (6.5)
`12 (9.7)
`43 (34.7)
`0
`
`37 (29.8)
`35 (28.2)
`52 (41.9)
`0
`
`2.0
`0, 80
`
`25 (20.2)
`81 (65.3)
`18
`
`7.0
`2,11
`10
`
`8.0
`1,12
`72 (58.1)
`79 (63.7)
`
`42
`18, 77
`
`273 (55.8)
`216 (44.2)
`
`245 (50.1)
`35 (7.2)
`36 (7.4)
`168 (34.4)
`5 (1.0)
`
`140 (28.6)
`142 (29.0)
`198 (40.5)
`9
`
`2.0
`0, 90
`
`115 (23.5)
`322 (65.8)
`52
`
`7.0
`1,11
`38
`
`7.0
`0, 12
`280 (57.3)
`319 (65.2)
`
`*For study entry, patients were required to have a UCDAI score between4 and 10, inclusive. However, a number of patients were enrolled in the
`study with scores outside of the range (<4 [n = 32] or >10 [n = 3]). Additionally, there were 38 patients for wnom the UCDAIscore at baseline
`could not be calculated. In the spirit of the ITT principal, all of these subjects were enrolled in the study and were Included in the modified ITT
`population analysis as long as they did not have normal histology orinfectiouscolitis (ie, If the patient was found to have active UC, which was
`the disease under study, then they were included in the primary analysis).
`‘Five patients had a baseline endoscopic Index score of O or 1 (2 in the placebo group, O In the 9 mg budesonide MMx group, 1 in the 6 mg
`budesonide MMxXgroup, and 2 in the Asacol group).
`‘Includes mesalamine, balsalazide, balsalazide sodium, and sulfasalazine.
`
`6 mg, and Asacol groups, respectively, versus 24.8% of
`patients in the placebo group. Subgroup analyses were
`performed for clinical improvementin patients with mild
`and moderatedisease. In patients with mild disease (UCDAI
`score 4-5 points), the clinical improvement rates in the
`placebo, budesonide MMX® 9 mg, budesonide MMX 6
`mg, and Asacol groups were 25.0%, 44.4%, 32.3%, and
`32.3%,
`respectively.
`In patients with moderate disease
`(UCDAI score 6-10 points),
`the clinical
`improvement
`rates in the placebo, budesonide MMX 9 mg, budesonide
`MMxX 6 mg,and Asacol groups were 30.1%, 39.7%, 34.2%,
`and 40.3%,
`respectively. Endoscopic improvement was
`achieved by 41.5%, 35.5%, and 33.1% of patients in the
`budesonide MMX 9 mg, budesonide MMX 6 mg, and
`Asacol groups, respectively, versus 33.1% of patients in the
`placebo group (P = .1746, P = .6846, and P = .9991,
`respectively) and should be considered nominal because
`statistical testing was not prespecified due to the hierar-
`
`chical testing procedures. Subgroup analyses for the ex-
`ploratory end point of mucosal healing (defined as UC-
`DAI mucosal appearance sub-score of 0) were performed
`for the categories of proctosigmoiditis, left-sided disease,
`and extensive disease. In patients with proctosigmoiditis,
`the mucosal healing rate for budesonide MMX 9 mg was
`numerically greater than that for placebo (32.4% vs 19.5%;
`P = .2031). Forleft-sided disease, the mucosal healing rate
`for budesonide MMX 9 mg was numerically greater than
`that for placebo (40.6% vs 26.5%; P = .2228). For extensive
`disease, the mucosal healing rate for budesonide MMX 9
`mg was numerically greater than that for placebo (16.1%
`vs 10.0%; P = .3914). For other prespecified end points,
`the percentages of patients achieving symptom resolution
`were significantly higher for the budesonide MMX 9 mg
`(28.5%) and 6 mg (28.9%) groups when compared with the
`placebo group (16.5%) (P = .0258 and P = .0214 for
`budesonide MMX 9 mg and6 mgversusplacebo, respec-
`Cosmo Ex. 2007-p. 4
`Argentum v Cosmo
`IPR2018-00080
`
`Cosmo Ex. 2007-p. 4
`Argentum v Cosmo
`IPR2018-00080
`
`

`

`1222 SANDBORNET AL
`
`GASTROENTEROLOGYVol. 143, No. 5
`
`tion, the rates of AEs and serious AEs leading to discon-
`tinuation were infrequent and similar across all study
`groups. There were no deaths during the study (Table 4).
`With regard to the AEs ofspecial interest, potential
`glucocorticoid effects occurred in similar percentages of
`patients across all treatment groups. Potential glucocor-
`ticoid effects were defined as the occurrence of one or
`more of the following symptoms: moon face, striae
`rubrae, flushing, fluid retention, mood changes, sleep
`changes, insomnia, acne, and hirsutism. There was no
`evidence of any increase in the numbersofpatients expe-
`riencing glucocorticoid effects in the budesonide MMX
`groups when compared with the placebo group. Potential
`glucocorticoid effects were observed in 10.1% of patients
`in the placebo group, 11.8% of patients in the budesonide
`MMxX 9 mggroup, 5.6% of patients in the budesonide
`MMxX 6 mg group, and 7.9% of patients in the Asacol
`group (Figure 2A).
`Although a decrease in mean morningplasmacortisol
`levels was observed at week 2 and week 4 for the budes-
`onide MMxXgroups,thelevels gradually increased toward
`the baseline values bythefinal visit. The mean percentage
`change from baseline to the final visit was — 17.9% in the
`budesonide MMX 9 mg group and —9.4% in the budes-
`onide MMX 6 mg group. By comparison, mean percent-
`age changes at thefinal visit were +0.9% in the Asacol
`group and +5.3% in the placebo group. Throughout the
`entire study period,
`the mean values in all treatment
`groups (including the budesonide MMX groups)
`re-
`mained within normal limits (5-25 g/dL) (Figure 2B).
`Furthermore,
`the observed changes in plasma cortisol
`were not associated with any increases in glucocorticoid-
`related effects across the budesonide MMXgroups. As
`noted previously, glucocorticoid effects occurred in a sim-
`ilar percentage of patients in the placebo, budesonide
`MMxX 9 mg,and budesonide MMX 6 mggroups.
`
`Discussion
`
`Treatment with budesonide MMX 9 mg showed a
`significant benefit over placebo in the rate of combined
`clinical and endoscopic remission at week 8 among pa-
`tients with active, mild to moderate UC. Exploratory anal-
`yses suggested a possible benefit for symptom resolution,
`and there were trends toward greater rates of clinical
`improvement and endoscopic improvement.
`Incidence
`rates of treatment-emergent adverse events were similar
`across treatment groups, and no clinically important
`safety trends were identified.
`Our results confirm the findings of another 8-week
`induction trial with budesonide MMxXin patients with
`active, mild to moderate UC showing that budesonide
`MMxX 9 mgwas effective for inducing combined clinical
`and endoscopic remission.** Similar to the current study,
`in that study there also were trends toward greater rates of
`clinical improvement and endoscopic improvement with
`budesonide MMxX,but the differences were notsignifi-
`cant. The discrepancy between the primary end point,
`Cosmo Ex. 2007-p. 5
`Argentum v Cosmo
`IPR2018-00080
`
`A.
`
`bar
`
`= Zr
`
`al
`bbo
`
`ra)
`
`remission
`Percent
`
`
`Percentsymptomresolution[QJ rpao
`
`Placebo
`
`MMX9mg MMX6mg
`
`Asacol
`
`*
`28.5
`
`*
`28.9
`
`25.0
`
`35
`
`30
`
`25
`
`__oa
`
`16.5
`
` o
`Placebo
`Asacol
`MMX9mg MMX6mg
`
`(A) Combined clinical and endoscopic remission at week 8.
`Figure 1.
`Modified ITT population, N = 489. *Statically significant (P < .025). (B)
`Symptom resolution at week 8. Modified ITT population, N = 489.
`*Statically significant (P < .05). This study was not powered to show
`a statistical difference between budesonide MMX treatment arms and
`Asacol.
`
`tively). The percentage of patients achieving symptom
`resolution was numerically higher for the Asacol (25.0%)
`group when compared with placebo, although it was not
`statistically significant (P = .1025) (Table 2). The percent-
`ages of patients with histologic healing were not signifi-
`cantly different between any active treatment group and
`placebo (Table 2).
`
`Safety
`Treatment with budesonide MMX® was generally
`well tolerated with an overall safety profile comparable to
`that of placebo. A similar proportion of patients in each
`study group experienced the most common treatment-
`emergent AEs (Table 3). Most patients experienced AEs
`that were mild or moderate in severity and were consid-
`ered notrelated to the study drug according to the inves-
`tigator evaluation. The percentage of patients with severe
`AEs was highest in the placebo group (12.4%) compared
`with the budesonide MMX 9 mg group (6.3%), budes-
`onide MMX 6 mg group (9.5%), and Asacol 2.4 g group
`(5.5%). The rates of treatment-related serious AEs were
`lowand occurred in similar percentages of patients across
`all treatment groups. There was no evidence of a dose
`trend for budesonide MMX with respect to the overall
`percentages of patients with AEsor serious AEs. In addi-
`
`Cosmo Ex. 2007-p. 5
`Argentum v Cosmo
`IPR2018-00080
`
`

`

`November 2012
`
`BUDESONIDE MMX® FOR INDUCTION OF REMISSION INUC 1223
`
`Table 2. Primary and Secondary End Points
`
`Combinedclinical and endoscopic remission, n (%)
`95% Cl
`Difference between active and placebo (%)
`95% Cl
`P value
`OR
`95% Cl
`
`Clinical improvement®
`Difference between active and placebo (%)
`P value
`Endoscopic improvement?
`Difference between active and placebo (%)
`Histologic healing?
`Difference between active and placebo (%)
`P value
`Symptom resolution?
`Difference between active and placebo (%)
`P value
`
`Placebo
`(n = 121)
`
`9 (7.4)
`2.8 to 12.1
`_—
`
`—
`_
`_
`
`30 (24.8)
`_—
`_
`40 (33.1)
`_—
`8 (6.6)
`—
`_—
`20 (16.5)
`_—
`_—
`
`Budesonide MMX9 mg
`(n = 123)
`
`Budesonide MMX6 mg
`(n = 121)
`
`_—Asacol 2.4 g
`(n = 124)
`
`22 (17.9)
`11.1 to 24.7
`10.4
`2.2 to 18.7
`01432
`2.71
`1.19 to 6.16
`41 (33.3)
`8.5
`.1420
`51 (41.5)
`8.4
`5 (4.1)
`-2.5
`.3759
`35 (28.5)
`11.9
`.0258°
`
`16 (13.2)
`7.2 to 19.3
`5.8
`—1.8 to 13.4
`.1393
`1.90
`0.80 to 4.48
`37 (30.6)
`5.8
`3146
`43 (35.5)
`2.5
`9(7.4)
`0.8
`8014
`35 (28.9)
`12.4
`.0214f
`
`CLINICALAT
`
`15 (12.1)
`6.4 to 17.8
`4.7
`—2.7 to 12.1
`.2200
`1.71
`0.72 to 4.08
`42 (33.9)
`9.1
`.1189
`41 (33.1)
`0
`14 (11.3)
`4.7
`.2003
`31 (25.0)
`8.5
`1025
`
`NOTE.This study was not powered to showa statistical difference between budesonide MMxXtreatment arms and Asacol.
`*Statistically significant (P < .025).
`‘Clinical improvement defined as a =3-point reduction In UCDAIfrom baseline to week 8.
`“Endoscopic improvement defined as a =1-point reduction in the mucosal appearance score of the UCDAI from baseline to week 8; statistical
`significance for endoscopic improvement was not tested due to prespecified hierarchical testing procedures.
`Other prespecified end points: “histologic healing defined as total histologic scoreof O or 1 for all biopsy specimens; “symptom resolution defined
`as UCDAI stool frequency and rectal bleeding subscoresof O.
`‘Statistically significant (P < .05).
`
`which was positive in both trials, and the secondary end
`points may be dueto therelatively high rates of clinical
`improvement and endoscopic improvement in patients
`receiving placebo. The reasonsfor these high placebo rates
`are not entirely clear but may relate to not using central
`reading for endoscopy measures, which can directly affect
`the mucosal appearance subscore and indirectly affect the
`physician’s rating of disease activity subscore, both of
`which then impact the overall UCDAI score. Notably, in
`both studies, exploratory analyses suggested that the rates
`of symptom resolution, which are based on the patient-
`reported components of the UCDAI, stool frequency and
`rectal bleeding, might be greater in patients treated with
`budesonide MMX® 9 mg as compared with placebo.
`Whenthese 2 studies were designed and the sample size
`
`was calculated, the available preliminary data of remission
`rates with budesonide MMX were based on a study by
`D’Haens et al that used the Clinical Activity Index,?7
`which does not include an endoscopic component. In the
`study by D’Haenset al, the clinical remission rate for
`budesonide MMX 9 mg, as measured by the Clinical
`Activity Index, was 47%.?4 We based the sample size cal-
`culationsfor the current trial on the assumption of a 20%
`difference between budesonide MMX andplacebo, which
`yields a placebo remission rate of 27% and an OR of1.7
`between budesonide MMX and placebo. However, in the
`current2 trials, the remission end point combinedclinical
`and endoscopic remission and was based on the UCDAI,
`not the Clinical Activity Index. The actual placebo remis-
`sion rates in these 2 trials were 7.4% and 4.5%, respectively,
`
`Table 3. Summary of Treatment-Emergent Adverse Events Experienced by =5.0% of Patients in Any Treatment Group
`
`Budesonide MMX 9 mg
`(n = 127)
`
`Budesonide MMX 6 mg
`(n = 126)
`
`Asacol 2.4 g
`(n = 127)
`
`74 (58.7)
`15 (11.9)
`17 (13.5)
`5 (4.0)
`6 (4.8)
`4 (3.2)
`5 (4.0)
`2 (1.6)
`5 (4.0)
`1 (0.8)
`
`80 (63.0)
`13 (10.2)
`12 (9.4)
`3(2.4)
`3 (2.4)
`2 (1.6)
`10 (7.9)
`10 (7.9)
`8 (6.3)
`7 (5.5)
`
`Cosmo Ex. 2007-p. 6
`Argentum v Cosmo
`IPR2018-00080
`
`MedDRApreferred term
`
`Any AE
`Colit